The present invention relates to the field of adhesive materials, and more particularly, to a novel composition-of-matter, a method of manufacturing thereof, and applications thereof as an adhesive, in a wide variety of different fields, and in particular, in the health care fields of medicine, dentistry, and veterinary science. The present invention is especially applicable for use by health care providers, such as medical, dental, and veterinary, surgeons, in procedures for reattaching or repairing body parts or components thereof, such as tissue, of (human or animal) subjects, especially under wet conditions, for example, involving adhesion of wet surfaces. The composition-of-matter of the present invention, being functional and usable as an adhesive, may also be functional and usable as a sealant or sealing agent, for sealing or closing an opening in a (dry or wet) surface.
Herein, for the purpose of clarity and consistency, it is to be fully understood that the term ‘adhesive’ is synonymous with the term ‘glue’, whereby each refers to a material or substance which exhibits adhesive properties, characteristics, and behavior. Accordingly, herein, an adhesive synonymously and equivalently refers to a glue, and use of the term adhesive is meant to generally encompass either such term.
In the health care fields of medicine, dentistry, and veterinary science, there are many procedures which are based on, or at least involve, reattaching or repairing body parts or components thereof, such as tissue, particularly, of a wound, for example, either as part of, or immediately following, performing surgery on a (human or animal) subject or treating a subject for trauma. Currently practiced tissue reattachment or repair procedures are ordinarily based on the use of sutures, staples, or/and wires. Although such procedures are well established and widely used, their applications often involve discomfort or/and pain to subjects. Moreover, the use of sutures for closing a wound typically results in the presence of unaesthetic remnant small openings in the skin. These limitations have led to the use of different materials, in particular, adhesives (glues), in medical procedures for reattaching or repairing tissue [1].
By using an adhesive in a tissue reattachment or repair procedure, typically, the adhesive needs to be applied onto a wet tissue surface, in particular, wetted by any combination of liquids, such as blood, water, and medicinal liquids, such as antiseptic or/and antibiotic liquids. The primary function of a ‘tissue’ adhesive is for binding and adhering tissues to each. As a direct consequence of binding and adhering tissues to each, the tissue adhesive performs a variety of secondary functions, in particular, stopping bleeding, sealing of leaks, and facilitating healing processes.
There are currently several types of commercially available tissue adhesives, made from synthetic or/and naturally existing components, in which these functions are performed, via in situ generation of a three-dimensional (3-D) polymeric network that is bonded to the tissue [2]. Cyanoacrylates [3], polyurethanes [4], gelatin based adhesives [2], fibrin based adhesives [1], and collagen based adhesives [5], are the most familiar commercially available tissue adhesives. The most widely used synthetic adhesives are cyanoacrylates, also known as ‘super glues’. They are applied as liquid monomers that polymerize on contact with tissue surfaces in an exothermic reaction creating a strong, yet flexible, film that bonds tissues of oppositely facing wound edges [3]. However, reported side affects, such as inflammatory response, delayed healing, necrosis, or/and thrombosis, limit their use as adhesives for internal organs [1]. Gelatin based adhesives form a network via crosslinking by resorcinol and formaldehyde. As with the cyanoacrylates, gelatin based adhesives are associated with toxicity issues [2]. Recently, there has been much effort to develop less toxic adhesives by using alternative materials, crosslinking chemistries, or controllable polymerization reactions, such as photo-initiated polymerization [6-12]. To date, none of these alternatives is commercially available.
The success of synthetic adhesives in a wet environment is limited, and typically requires carefully cleaned surfaces, which often must also be chemically treated and/or partially dried [13]. On the contrary, most adhesion events in nature occur under water. Many marine sessile organisms, such as mussels, barnacles, and tube worms, effectively stick to almost any wet surface [14]. Although a natural adhesive, such as ‘mussel glue’, made from naturally existing adhesive substances, in particular, proteins and polypeptides, obtained from these organisms, has been claimed to be suitable for medical applications, including, for example, during wet conditions, it is clear that commercial production of such a mussel glue is currently not practical, since, for example, extraction of 1 kg of the naturally existing adhesive raw materials (proteins and polypeptides) would require processing five to ten million mussels [1].
Another, yet equally effective natural adhesion mechanism exists in red and brown algae, which produce phenolic compounds that exhibit adhesive properties, characteristics, and behavior, and extraordinarily high cohesive strengths. These adhesive phenolic compounds bind non-specifically to both hydrophobic and hydrophilic surfaces in aqueous conditions [15]. Vreeland et al. [16] postulated that initial substratum adhesion by zygotes of the brown alga Fucus gardenri involves the secretion of polyphenols. Later on, these polyphenols are activated by a vanadate peroxidase type of enzyme catalyst for enabling cross-linking of polyphenols to extra cellular carbohydrate fibers, eventually leading to formation of an algal adhesive.
Vreeland, et al. [17] disclose various formulations of a water-resistant, aqueous, phenolic adhesive or glue derived from algal raw materials. The phenolic component of the disclosed adhesives is an algal phloroglucinol-based polyphenolic compound, containing from about 2 to 500,000 phloroglucinol (1,3,5-trihydroxybenzene) units, wherein the phloroglucinol units are joined by carbon-carbon bonds or by ether linkages. The algal derived adhesive polyphenolic compounds are preferably activated with an enzyme catalyst, such as vanadate-requiring peroxidase, horse radish peroxidase, mushroom polyphenoloxidase, or other oxidoreductase, or, by addition of an oxidizing agent, such as sodium hypochlorite, hydrogen peroxide, urea hydrogen peroxide, sodium hypochlorite, periodic acid, nitric acid, potassium permanganate, or potassium dichromate. The activated polyphenolic compound may be cross-linked with various natural or synthetic macromolecules, such as carbohydrates (for example, alginate or fucoidans), proteins, or fibers.
Covalent cross-linking of phenols to a substrate is also possible. Recently, Berglin, et al. [18] studied the enzymatic cross-linking of a phenolic polymer extracted from the alga Fucus serratus using the quartz crystal microbalance with dissipation monitoring methodology (QCM-D). Their results show that addition of a vanadium-dependent haloperoxidase enzyme, in particular, bromoperoxidase (BPO), along with potassium bromide (KBr), and hydrogen peroxide (H2O2), to the phenolic polymer, caused a decrease in dissipation, indicating that a cross-linking process may have occurred. Although all four components were proven to be necessary, the cross-linking mechanism remained unclear. The work by Berglin et al. has demonstrated the potential feasibility of using algal phenolic polymers as a component in a tissue adhesive.
Algal derived natural adhesives, such as the algal phloroglucinol-based polyphenolic adhesives disclosed by Vreeland, et al. [15, 17], have the same limitation regarding feasible commercial production, as for the previously described marine organism derived natural adhesives, such as mussel glue. An enormous quantity of brown algae is required for extracting a significantly smaller quantity of the naturally existing adhesive raw material (polyphenols). Moreover, once a suitable quantity of the naturally existing adhesive raw material (polyphenols) is made available, producing a ‘usable’ final form of such an algal derived natural adhesive requires performing a relatively long sequence of various chemical and physical separation and purification processes and procedures, which further brings into question the commercial feasibility and applicability of such natural adhesives.
Instead of attempting to produce a commercially feasible quantity of a natural adhesive, from naturally existing adhesive raw materials, such as proteins, polypeptides, or polyphenols, requiring processing an enormous quantity of a marine or aquatic organism, followed by having to perform a relatively long sequence of various chemical and physical separation and purification processes and procedures, an alternative and more practical method is based on taking a ‘biomimetic’ approach, whereby polymeric analogs are synthesized from amino acids that were identified in naturally existing adhesive proteins [13]. Much effort has been made to synthesize random block copolymer biomimetic approximations of naturally existing adhesive proteins and polypeptides. These attempts include synthesis of sophisticated peptide sequences identified in adhesive proteins of mussels [19], co-polypeptides containing DOPA [13], DOPA-modified polyethyleneglycol hydrogels [20], and DOPA modified pluronics [21]. However, to date, adhesive strengths achieved for biomimetic adhesives, for example, mussle glue imitations, have not been sufficient to stimulate interest in large-scale industrial production. Moreover, biomimetic adhesives have rarely been applied and cured on test surfaces located under water [22].
Based on the above stated disadvantages of using sutures, staples, or/and wires, in currently practiced tissue reattachment or repair procedures, and the above described limitations associated with currently commercially available tissue adhesives made from synthetic or/and naturally existing components, and limitations associated with natural adhesive formulations made from marine or aquatic organisms, as well as limitations associated with biomimetic approximations of natural adhesives, there continues to be an on-going need for developing new adhesives (glues), particularly in the health care fields of medicine, dentistry, and veterinary science, for use by health care providers, such as medical, dental, and veterinary, surgeons, in procedures for reattaching or repairing body parts or components thereof, such as tissue, especially under wet conditions, for example, involving adhesion of wet surfaces.
There is thus a need for, and it would be highly advantageous to have, a novel composition-of-matter, a method of manufacturing thereof, and applications thereof as an adhesive. There is a particular need for such an invention which is safe and effective for use on (human or animal) subjects, and which is especially applicable in the health care fields of medicine, dentistry, and veterinary science, for use in procedures for reattaching or repairing body parts or components thereof, such as tissue, especially under wet conditions, for example, involving adhesion of wet surfaces. There is additional need for such an invention which is commercially feasible and applicable, which doesn't require processing an enormous quantity of a marine or aquatic organism, followed by having to perform a relatively long sequence of various chemical and physical separation and purification processes and procedures, for producing a usable final form of the inventive adhesive.
There is additional need for such an invention wherein the composition-of-matter, being functional and usable as an adhesive, may also be functional and usable as a sealant or sealing agent, for sealing or closing an opening in a (dry or wet) surface, for example, for preventing flow of a (liquid or/and gaseous) fluid through the sealed or closed portion of the surface. Moreover, there is a need for such an invention which is generally applicable in a wide variety of different fields, in addition to the health care fields.